Problem Solving in Cancer and Fertility

By EBN Health

The treatment of cancer in young women and men is increasingly turning from focusing purely on survival to a recognition of the long-term effects of treatment on subsequent quality of life. In this regard, fertility is a very high priority for patients. This is the first book to explain the latest techniques in fertility preservation. Chapters c

• Language: English
• Publisher: EBN Health
• Release date: Dec 11, 2020
• ISBN: 9781739881450

Book preview

S E C T I O N   O N E 01

PERSPECTIVE

01 The Effects of Cancer and its Treatment on Female Fertility

Richard A. Anderson

Introduction

The treatment of cancer in young women is increasingly turning from focusing purely on survival to recognition of the long-term effects of treatment on subsequent quality of life. In this regard, fertility is a very high priority for patients. That cytotoxic therapies have adverse effects on fertility has been recognized since the very earliest days of the administration of mustard gas derivatives, and specifically in relation to the ovary, with demonstration of the effects of chemotherapeutic agents on growing follicles, resulting in amenorrhea, and in the longer term resulting in loss of fertility and premature menopause. Pregnancy after cancer is also associated with increased risk, notably of prematurity and low birth weight.¹ The recognition of the importance of late effects on fertility have been paralleled by a substantial growth in the development and provision of fertility preservation services in reproductive medicine centres and the development of the necessary close links with oncology and other services, although this remains an area where much work needs to be done in improving awareness and access to services in the UK. Fertility preservation is a complex area, requiring a balance between accurate identification of those at risk and the provision of a sufficiently encompassing service, with issues including equality of access, informed decision making regarding the experimental nature of some procedures and provision of funding. From the patient’s perspective, this is all undertaken at very short notice at a time of enormous stress following a recent diagnosis when many other tests and investigations also need to be undertaken. Subsequent fertility is also part of a broader survivorship agenda, recognizing that most cancer survivors have significant health issues which may impact directly or indirectly on their fertility, for example the recognition that survivors of brain and CNS cancers have reduced chance of marriage or co-habitation. There may additionally be concerns about starting or completing a family following such a serious diagnosis, as well as concerns, now recognized to be unsubstantiated, that a pregnancy following, for example breast cancer may increase the risk of recurrence.

Recent developments

The effects of chemotherapeutic agents on the ovary will almost invariably involve loss of the growing population of follicles, related to their rapid cell proliferation and sensitivity to cytotoxic agents. This is likely to result in a rapid decline in oestrogen levels, and often amenorrhea. However it is the risk to the non-growing primordial follicle pool that is most important in determining the long-term effects, and potential recovery of the ovary,² as they constitute the ‘ovarian reserve’. Primordial follicles are formed in fetal life and thereafter a small proportion start to grow every day; subsequently the growing follicles develop fluid-filled cavities (antra) and increasingly produce oestrogen, culminating in ovulation. The number of primordial follicles is therefore progressively depleted over time, with near-exhaustion resulting in the menopause. Premature loss of primordial follicles, as occurs with some chemotherapies, will therefore bring forward the time of the menopause, ultimately during or shortly after treatment. Remaining primordial follicles will start to grow, thus ‘repopulating’ the growing follicle populations of the ovary, with restoration of menses and fertility. This may however be short-lived. Additionally, while the follicle pool is the most important target within the ovary, effects on the vasculature and ovarian stroma are also very relevant and may significantly comprise later follicle growth: these may be affected by chemotherapy as well as radiotherapy. These effects of treatment are depicted in Figure 1.1.

fig

Figure 1.1 Representation of the effects of gonadotoxic treatment on the ovary. The number of primordial and early growing follicles in a healthy ovary is reduced by some chemotherapy regimens, with additional effects on the ovarian vasculature and stroma. If a sufficient population of primordial and thus early growing follicles remains, development of pre-ovulatory follicles will continue allowing the potential for post-treatment fertility. Otherwise, complete depletion results in premature ovarian insufficiency (POI), infertility and oestrogen deficiency. Ongoing post-treatment ovarian function may develop into POI, depending on the remaining ovarian reserve.²

As the primordial follicle pool can only be determined histologically, many studies rely on surrogate biochemical or clinical outcomes. These include anti-müllerian hormone (AMH), which is produced by the smaller antral follicles (Figure 1.1), ultrasound measures of the antral follicle count and most commonly the presence or absence of menses, commonly recorded as chemotherapy related amenorrhea. AMH has become the most useful biomarker of the ovarian reserve in this and other clinical situations, particularly as it does not vary to an important degree across the menstrual cycle. It does however vary in other important clinical situations, most notably being reduced by perhaps as much as 30% in women taking the combined contraceptive pill, and may also be reduced in women with cancer at the time of diagnosis. The more important clinical outcomes are much more difficult to determine and include fertility and age at menopause, with other patient-critical outcomes such as time to pregnancy and attaining desired family size, rarely if ever described. The endocrine-related functions of the ovary, for example in supporting bone mass and quality of life through recording of issues such as hot flushes and joint pains, are also sometimes investigated and are important aspects of the non-reproductive aspects of ovarian function.

In addition to the ovary, the uterus is also a key target of damage through radiotherapy to the pelvis, particular before puberty. Radiotherapy damage to the uterus may result in early or late miscarriage, premature delivery, stillbirth and post-partum haemorrhage.³ The central control pathways of the hypothalamus and pituitary may also be damaged by surgery or cranial radiotherapy, with sometimes subtle but progressive effects on ovulatory control reported.

Due to the progressive decline in the number of follicles within the ovary with age, and the variability from one woman to the next, treatment effects are superimposed on a very wide-ranging background level of ovarian function. The effect of age is well-described, with data showing an increased prevalence of infertility with increasing age at diagnosis even in women with ongoing ovarian function, as well as changes in the prevalence of post-treatment amenorrhea. There are limited data on risk of early menopause, but for example in the case of Hodgkin’s lymphoma, the varying risk with different therapies has been clearly described with minimal risk of early menopause following ABVD therapy, but with substantial and increasing risk with alkylating based therapy, pelvic radiotherapy and particularly the combination.⁴ Data relating to fertility after cancer therapy are more scarce, and better provided in the paediatric than adult setting. The United States Childhood Cancer Survivors Study has provided considerable data for many years now, and recent data on women treated with chemotherapy only show the importance of specific therapies but against an overall positive finding of a hazard ratio for live birth of 0.87 (95% CI 0.81–0.92).⁵ That analysis does however highlight the effect of later age at conception, with a widening of the difference between cancer survivors and their siblings in women who had not conceived before the age of 30. To broaden these data and provide an unbiased risk, we undertook an analysis of population based databases in Scotland recording all diagnoses of cancer up to the age of 40 against subsequent pregnancies, with outcomes compared to the general population standardized for age at diagnosis, interval since and deprivation.⁶ Overall, this showed that women were 38% less likely to achieve a pregnancy after a cancer diagnosis than women in the general population and this was across all diagnostic groups (Figure 1.2). Cervical and breast cancer made the greatest impact with standardized incidence ratios of 0.34 and 0.39, respectively, but in both cases there have been substantial improvements in the likelihood of achieving a pregnancy across the period of analysis from 1981 to 2012, particularly for cervical cancer (Figure 1.3). This may be an effect of the introduction of cervical screening and thus earlier, less aggressive surgical treatment for cervical cancer, and changes in chemotherapy regimens for breast cancer. For other diagnoses, notably leukaemia and brain/CNS cancers, there has not been any apparent improvement in the chance of pregnancy after diagnosis over these years. Perhaps indicating greater health-awareness after cancer, this analysis also showed that the likelihood of a pregnancy resulting in termination was, in fact, significantly reduced following a cancer diagnosis, particularly in those diagnosed in childhood and adolescence. There were additional improvements in the mode of delivery, with a normalization of the rate of elective caesarean section.¹

fig

Figure 1.2 Standardized incidence rate (SIR, with 95% CI) for pregnancy after cancer by diagnosis. Data are for female patients (n = 23,201) diagnosed below the age of 40 years between 1981 and 2012 in Scotland, with subsequent pregnancies or death up until the end of 2014, compared to population controls. Standardized for age, deprivation and year of diagnosis. Data from Ref. (6).

fig

Figure 1.3 Adjusted hazard ratio (HR, with 95% CI) for first pregnancy after cancer diagnosis by period of diagnosis for women with breast, Hodgkin’s lymphoma, cervical, leukaemia and brain/CNS cancers. Reprinted with permission from Ref. (6).

There has been much interest in the value of the measurement of AMH as an index of cancer treatment induced damage to the ovary, first demonstrated in survivors of childhood cancer despite their continuing to have regular menstrual cycles.⁷ This finding has been replicated in many other studies and it has also been shown that pre-treatment AMH will predict long-term ovarian function, particularly in the context of breast cancer treatment.⁸ In that study, all women with pre-treatment AMH <1.9 ng/ml (13.5 pmol/l) showed long-term amenorrhoea, and a value of 0.71 ng/ml (5.0 pmol/l) had peak likelihood ratio of 7 for predicting ongoing menses, with sensitivity 54% and specificity 92%. AMH very clearly distinguishes between high and low risk gonadotoxicity treatments, for example comparing ABVD treatment with BEACOPP: there is complete recovery of AMH levels in women treated with ABVD but only very low post-treatment levels following BEACOPP.⁹ Intriguingly, however, even following ABVD there was evidence of an impact of age on the rate and extent of recovery, with compromised recovery in women over the age of 35.

While other articles in this series will discuss approaches to fertility preservation, it is now clear from several large randomized control trials that GnRH agonist treatment during chemotherapy for breast cancer does reduce the prevalence of premature ovarian insufficiency thereafter.¹⁰ Meta-analysis indicates an odds ratio of 0.37, with a very similar result from an individual patient data analysis approach, with an odds ratio of 0.38. However, it is important to recognize that these studies only followed-up women for relatively short periods of time, generally no longer than 2 years, and therefore the true benefits of this apparent protective effect on either fertility or the non-reproductive endocrine aspects of ovarian function have not been clearly determined. Notably, the OPTION trial was the only large randomized controlled trial to include AMH measurement to assess ovarian reserve post-treatment, and this showed no difference in AMH levels following recovery between those who did or did not have GnRH agonist treatments during chemotherapy.¹¹ A wide range of other pharmacological approaches to protect the ovary are also being investigated, but these remain in the pre-clinical stage.

Conclusion

hand Fertility preservation is now a part of mainstream medicine, which recognizes the importance of fertility after cancer treatment to many women. There is an ongoing need for improved accuracy of patient-specific assessment of risk to their fertility and ovarian function, focusing on their proposed treatment, but also in the context of intrinsic issues, notably their age and ovarian reserve. It is to be hoped that in the future, this will allow more tailored and effective use of fertility preservation techniques, with long-term outcome studies also addressing the non-reproductive health benefits of improved ovarian function.

References

1 van der Kooi ALF, Kelsey TW, van den Heuvel-Eibrink MM, et al. Perinatal complications in female survivors of cancer: a systematic review and meta-analysis. Eur J Cancer 2019; 111: 126–37.

2 Jayasinghe YL, Wallace WHB, Anderson RA. Ovarian function, fertility and reproductive lifespan in cancer patients. Expert Rev Endocrinol Metab 2018; 13(3): 125–36.

3 Signorello LB, Mulvihill JJ, Green DM, et al. Stillbirth and neonatal death in relation to radiation exposure before conception: a retrospective cohort study. Lancet 2010; 376(9741): 624–30.

4 Swerdlow AJ, Cooke R, Bates A, et al. Risk of premature menopause after treatment for Hodgkin’s lymphoma. J Natl Cancer Inst 2014; 106(9): dju207.

5 Chow EJ, Stratton KL, Leisenring WM, et al. Pregnancy after chemotherapy in male and female survivors of childhood cancer treated between 1970 and 1999: a report from the Childhood Cancer Survivor Study cohort. Lancet Oncol 2016; 17(5): 567–76.

6 Anderson RA, Brewster DH, Wood R, et al. The impact of cancer on subsequent chance of pregnancy: a population-based analysis. Hum Reprod 2018; 33(7): 1281–90.

7 Bath LE, Wallace WH, Shaw MP, Fitzpatrick C, Anderson RA. Depletion of ovarian reserve in young women after treatment for cancer in childhood: detection by anti-Mullerian hormone, inhibin B and ovarian ultrasound. Hum Reprod 2003; 18(11): 2368–74.

8 Anderson RA, Cameron DA. Pretreatment serum anti-mullerian hormone predicts long-term ovarian function and bone mass after chemotherapy for early breast cancer. J Clin Endocrinol Metab 2011; 96(5): 1336–43.

9 Anderson RA, Remedios R, Kirkwood AA, et al. Determinants of ovarian function after response-adapted therapy in patients with advanced Hodgkin’s lymphoma (RATHL): a secondary analysis of a randomised phase 3 trial. Lancet Oncol 2018; 19(10): 1328–37.

10 Lambertini M, Moore HCF, Leonard RCF, et al. Gonadotropin-releasing hormone agonists during chemotherapy for preservation of ovarian function and fertility in premenopausal patients with early breast cancer: a systematic review and meta-analysis of individual patient-level data. J Clin Oncol 2018; 36(19): 1981–90.

11 Leonard R, Adamson D, Bertelli G, et al. GnRH agonist for protection against ovarian toxicity during chemotherapy for early breast cancer: the Anglo Celtic Group OPTION trial. Ann Oncol 2017; 28(8): 1811–6.

PERSPECTIVE

02 Fertility Preservation in Women

Julia Kopeika

Introduction

As many as 10% of adults diagnosed with cancer in the UK are in the reproductive age between 25 and 49 years. There are twice as many cancer cases in women of this age group in comparison with men (Cancer Research UK). Advances in anti-cancer therapy have resulted in improved survival promoting a greater focus on quality of life issues, of which future fertility plays an integral role. The age of childbearing has become progressively older (Office of National Statistics) and as such many of these women may not have even started or completed their family.

Several options for fertility preservation (FP) could be considered in female patients depending on their age, ovarian reserve, type of cancer, timeframe (urgency of need to start treatment) and their wishes.

The following FP options are available:

1) Eggs/embryos freezing

2) Ovarian tissues preservation and transplantation

3) Medical protection with gonadotropin-releasing hormone (GnRH) agonists

This chapter will cover current available options, explain principles of controlled ovarian stimulation (COS) and discuss risks and benefits of different methods. In addition, data on national UK experience will be presented.

Recent developments

The option of egg/embryo freezing requires COS. The main principles of COS are based on the following:

1) Administration of FSH above the natural FSH threshold for follicular recruitment. The follicle-stimulating hormone (FSH) threshold is the level that initiates the final stage of follicular development from the early antral to pre-ovulatory stage of the dominant follicle.

2) Extending the ‘FSH window’. The duration of the rise in FSH above a critical threshold governs the number of dominant follicles selected from the recruited cohort for preferential growth.¹ This is the ‘FSH Window Concept’.² The duration of FSH above the threshold is short in the natural cycle, as newly growing follicles trigger the drop in FSH level through negative feedback. This drop results in only one follicle maintaining the ‘energy’ of growth which eventually results in a single dominant follicle capable of ovulation. Widening the ‘FSH window’ allows multiple follicles to be selected at the same time. Artificially administered FSH in constant amounts, which consistently exceed the natural threshold level, allows sustained multiple follicular development during COS (Figure 2.1).

fig

Figure 2.1: FSH levels and follicular recruitment in a natural cycle in comparison with a cycle of controlled ovarian stimulation.

3) Controlling the time of ovulation. Adequately grown follicles are capable of triggering release of luteinizing hormone (LH) which eventually governs the completion of the oocyte maturation process and ovulation. To improve the efficiency of COS, the natural release of LH is blocked and an artificial ovulation trigger is given to time the egg collection 36 h later. By this time the follicles will have gained all the necessary competencies of mature eggs, but their release will not yet take place. Hence all mature eggs derived from ovarian stimulation can be collected simultaneously and preserved for future use.

The whole process of COS takes approximately 11–14 days. Women would be expected to attend for an ultrasound scan two to three times during the whole process. Once the growth of all recruited follicles has reached the optimal size, the individual would be instructed to have the trigger injection (GnRH agonist) and attend for egg collection; this is usually a day case procedure under sedation.

The difference between urgent FP and general in vitro fertilization (IVF) patients is that there is no requirement for synchronization of endometrium development and egg collection; hence the stimulation can be started at any time of the menstrual cycle rather than limited between days 2 and 4. This provides a significant advantage in timeframes without compromising the number or quality of collected eggs.

The overall risks from COS are very low. There may be no eggs or a poor response, or a need for cycle cancellation (this applies to women with poor ovarian reserve and in most cases could be anticipated) as well as ovarian hyperstimulation syndrome (OHSS). OHSS is associated with hypercoagulation and thrombosis, ascites and deranged liver and kidney function. The modern methods of stimulation with a GnRH agonist trigger can almost eliminate OHSS.³ The egg collection, in common with other surgical procedures, is associated with vaginal bleeding (5%), infection (0.9%), internal bleeding (0.05%) and damage to intestine (0.001%).

Some specific considerations may be needed with different types of cancer (see Table 2.1).

Table 2.1: Risks associated with different malignancies.

The long-term effect of FP is poorly reported. The current limited data are reassuring with no evidence of a decline in relapse-free survival rates in two studies of women with breast cancer who received COS compared with women who did not.⁴ In our unpublished data, the mortality rate was under 10% in 451 patients who pursued FP, mainly with breast, gynae and GI cancers, after an average follow up of 7.3 years; this was similar to those who opted not to have FP. The mortality rate was adjusted by tumour type.

The slow-freezing method of gamete preservation provided promising results with the first birth from a frozen human embryo being reported in 1983. In 1985 another fast freezing method, called vitrification, appeared as a potential solution for poor outcomes of the oocyte slow freezing process. It was not until 1999, when the first birth was reported from a vitrified oocyte. Twenty years on, sufficient data are available which show that oocyte vitrification can provide very similar results to the embryo freeze programme.⁵ In 2018, the Human Fertilisation and Embryology Authority (HFEA) reported the live birth rate from oocytes was only 3% lower as compared to frozen embryos. Therefore, single young patients, faced with gonado-destructive treatment, can be reassured that they will not be disadvantaged by preserving their unfertilized eggs. Furthermore, for young patients who do attend with partners and appear to be keen to preserve embryos, caution is required as frozen embryos belong to both partners. Should one of the partners withdraw consent at a later stage, the fertilized embryos cannot be used by the other partner whatever the circumstances. Data from young donor patients, less than 35 years, demonstrate retrieval of 10–12 eggs and a live birth rate between 39% and 53%.⁶

Ovarian tissue cryopreservation prior to chemotherapy is another option for FP which has been emerging over several decades. Although progress has been slow, it has a place in FP for women who need urgent treatment or who are physiologically immature (pre-pubertal girls). The first infant from frozen-thawed ovarian tissue was born in 2004. The technology has been offered as a part of the FP options across Europe, US, Australia and Canada for more than a decade.⁷ In the UK, only a very limited number of centres offer this valuable option. The main risks associated with the process are associated with laparoscopic surgery for collection and re-implantation, as well as process failure. Recent evidence demonstrated that the live birth-rate from transplanted ovarian tissues was similar to that from vitrified eggs.⁸ Moreover, woman with ovarian tissue transplantation not only resumed their ovarian endocrine function but also had a high rate of spontaneous pregnancy (46%).⁸ This technique may not be suitable for all types of tumour.

The most intriguing direction lies in the development of mitigation strategies is to diminish off-target effect of chemotherapy and radiotherapy. Attempts to encapsulate chemotherapy drugs within nanoparticles, inhibit early apoptotic events in primordial follicles or apply immunomodulators to protect the pool of follicles have been tested in animal models.⁹

Administration of GnRH agonists during chemotherapy represents a standard method of FP although debatable and controversial. It blocks the reproductive axis and restricts chemotherapeutic-induced primordial follicle death; however the mechanism is unclear. An analysis of 14 randomized controlled trials involving a total of 1647 patients with breast cancer showed that the risk of premature ovarian insufficiency was reduced. Conversely, there was no benefit in FP with GnRH agonist in much younger women with lymphoma (smaller study with 154 subjects).¹⁰

As more effective methods of FP become available, fertility restoration becomes an increasingly important area of care for young women with cancer. However, there is inconsistency of funding criteria across the country which causes discrepancy in access. The Guy’s and St Thomas’ Assisted Conception Unit surveyed all 209 Clinical Commissioning Groups (CCGs) in 2018 regarding assisted conception funding (unpublished data). The survey concluded that:

• Nearly half of CCGs apply general IVF age criteria which is not consistent with Fertility NICE guidelines (2013).

• There is marked variation and inconsistency by regions.

• Processing times of FP applications in some areas can take up to 2 months.

• The majority of CCGs do not hold information on the number of FP cycles; thus it is difficult to assess the total national number of patients who could benefit from the service.

Based on limited information, it is estimated that approximately 454 cycles of FP were funded by 40% of CCGs in England over a period of 2 years, whereas as many as 35,000 women of reproductive age were diagnosed with cancer over the same period.

Conclusions

hand • Current COS protocols with a random start are tailored to minimize delay of systemic anti-cancer treatment with minimal side-effects.

• Egg or embryo freezing should be completed within 2–3 weeks with well-established pathways and direct communication between cancer care providers and fertility clinics.

• The limited long-term data on egg freezing show similar